Dominant Role of the p110β Isoform of PI3K over p110α in Energy Homeostasis Regulation by POMC and AgRP Neurons

• DOI: 10.1016/j.cmet.2009.09.008
• Publication Date: 2009-11-04T09:24:51Z
• Authors: Hind Al-Qassab; Mark A. Smith; Elaine E. Irvine; Julie Guillermet-...; Marc Claret; Agharul I. Choudhury; Colin Selman; Kaisa Piipari; Melanie Clements; Steven Lingard; Keval Chandarana; Jimmy D. Bell; Gregory S. Barsh; Andrew J.H. Smith; Rachel L. Batterham; Michael L.J. Ashford; Bart Vanhaesebroeck; Dominic J. Withers
• Keywords: Leptin; 0301 basic medicine; FOOD-INTAKE; EXPRESSING NEURONS; 570; /dk/atira/pure/subjectarea/asjc/1300/1314; Pro-Opiomelanocortin; /dk/atira/pure/subjectarea/asjc/1300/1312; Physiology; Class I Phosphatidylinositol 3-Kinases; HUMDISEASE; Hypothalamus; 610; PHOSPHOINOSITIDE 3-KINASE; Article; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; LEPTIN; Neuroendocrine Cells; Animals; Insulin; Agouti-Related Protein; Obesity; HYPOTHALAMIC ARCUATE NUCLEUS; Molecular Biology; Adiposity; Phosphoinositide-3 Kinase Inhibitors; Mice, Knockout; INSULIN SENSITIVITY; Cell Biology; Diet; Electrophysiological Phenomena; Isoenzymes; MICE; BODY-WEIGHT; INDUCED ANOREXIA; Energy Metabolism; /dk/atira/pure/subjectarea/asjc/1300/1307; PROOPIOMELANOCORTIN NEURONS; Signal Transduction

PI3K signaling is thought to mediate leptin and insulin action in hypothalamic pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, through largely unknown mechanisms. We inactivated either p110alpha or p110beta PI3K catalytic subunits in these neurons and demonstrate a dominant role for the latter in energy homeostasis regulation. In POMC neurons, p110beta inactivation prevented insulin- and leptin-stimulated electrophysiological responses. POMCp110beta null mice exhibited central leptin resistance, increased adiposity, and diet-induced obesity. In contrast, the response to leptin was not blocked in p110alpha-deficient POMC neurons. Accordingly, POMCp110alpha null mice displayed minimal energy homeostasis abnormalities. Similarly, in AgRP neurons, p110beta had a more important role than p110alpha. AgRPp110alpha null mice displayed normal energy homeostasis regulation, whereas AgRPp110beta null mice were lean, with increased leptin sensitivity and resistance to diet-induced obesity. These results demonstrate distinct metabolic roles for the p110alpha and p110beta isoforms of PI3K in hypothalamic energy regulation.